POS0403 DYNAMIC CHANGES IN AUTOREACTIVE MEMORY B CELLS IN RHEUMATOID ARTHRITIS: KEY TO UNDERSTANDING IMMUNOLOGICAL DISEASE ACTIVITY
Authors: N. Blomberg, H. Kristyanto, M. Verstappen, S. Neppelenbroek, A. S. B. Kampstra, A. Van der Helm-van Mil, R. Toes, H. U. Scherer
Journal: Annals of the Rheumatic Diseases (2022)

Background Rheumatoid arthritis (RA) patients with autoantibodies against citrullinated antigens (ACPA) are characterized by poor chances to achieve sustained DMARD free remission. We have previously observed that autoreactive ACPA-expressing memory B cells (MBC) display an activated phenotype and frequently maintain this state of activation even in patients in clinical remission in whom joint inflammation is absent through treatment. Conceptually, these observations could reflect ongoing immunological activity. In fact, they indicate that most current therapeutic interventions do not induce immunological remission and could explain why disease frequently flares when treatment is stopped. ACPA-expressing MBC display the phenotype of recent germinal centre emigrants, actively proliferating (Ki-67 positive), expressing CD95 and co-stimulatory markers CD80 and CD86, and the signature cytokine IL-8.[1] Notably, in autoantibody-positive individuals with arthralgia that did not progress to inflammatory arthritis within 2 years, the autoreactive B cells were readily detectable in the circulation and proliferated but lacked, in most cases, the upregulation of CD80 seen at the onset of disease. Now, we studied these autoreactive B cells longitudinally in the ‘at-risk’ phase of clinically suspect arthralgia (CSA) and in a population of patients in sustained (&gt;1 year) drug-free remission (SDFR). Objectives To define dynamic changes of the ACPA-expressing B cell compartment throughout clinical disease stages with the aim to evaluate this response as a possibly predictive biomarker of immunological disease activity. Methods ACPA-expressing MBC were identified by flow cytometry in peripheral blood of RA patients with chronic disease or at disease-onset (treatment-naïve), in ACPA-positive CSA patients ‘at-risk’ for RA, and in patients in SDFR. B cells were characterized by a combination of markers to classify B cell subpopulations and activation- and germinal centre related markers. Tetanus-toxoid-specific B cells were analysed in the same individuals as antigen-specific comparators. Results In patients in SDFR, significantly less autoreactive B cells expressed CD80 compared to active disease, while they persistently showed signs of proliferation, similar to the phenotype observed in CSA patients that did not progress to RA. ACPA-specific plasmablasts (defined as CD20 - CD27 hi ) were practically absent in SDFR and CSA non-progressors, while they were readily detectable in patients with RA at disease onset, during treatment, and in CSA-individuals that later progressed to RA. Notably, two arthralgia patients that developed RA within one year showed high CD80 expression in the autoreactive MBC compartment already in the ‘at-risk’ phase, whereas patients that so far did not progress to RA during the time of follow-up, showed less CD80-positive autoreactive MBC. Conclusion The phenotype of autoreactive B cells is dynamic in different disease phases of RA. By studying extremes of clinical phenotypes (‘at-risk’ phase, disease onset, SDFR), we found evidence for dynamic expression of CD80 by ACPA-expressing MBC in relation to clinical disease stage. Intriguingly, CD80-positive B cells, but not CD80-negative B cells, have been shown to be able to differentiate into antibody secreting cells in mice.[2] Our finding that plasmablasts were practically absent in ACPA-positive arthralgia patients that did not progress to RA and in SDFR would fit with this notion and suggests that in SDFR autoreactive MBC lack, although actively proliferating, triggers that induce CD80 upregulation, differentiation to plasmablasts and, possibly, their active participation in processes causing joint inflammation. Based on this observation, it is possible that induction of this CD80 lo phenotype in autoreactive MBC may be an important step towards achieving immunological remission, a conceptual proxy for cure. References [1]H. Kristyanto et al. , Sci Transl Med 12 , (2020). [2]G. V. Zuccarino-Catania et al. , Nat Immunol 15 , 631-637 (2014). Disclosure of Interests None declared.